Browsing by Subject "baroreflex"
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Item Brainstem mechanisms that impair autonomic regulation of blood pressure with obesity(2018-12) Chaudhary, Parul; Schreihofer, Ann M.; Mifflin, Steve W.; Cunningham, J. Thomas; Schreihofer, Derek A.Metabolic syndrome (MetS) is emerging as a global health threat due to its strong association with increased risk for cardiovascular disease and diabetes. Currently, 20-25% of the world's population exhibits some traits of MetS, namely obesity, dyslipidemia, hyperinsulinemia, hypertension, and hyperglycemia. In addition, MetS also promotes the development of impaired short-term regulation of mean arterial pressure (AP) by baroreflexes, which normally act to stabilize AP. The resulting increased AP variability, which is an independent risk factor for poor outcomes, is overlooked as a trait of MetS and goes without evaluation or treatment. People who have controlled hypertension without minimizing elevated AP variability are still at significant risk for detrimental cardiovascular events such as stroke and cognitive decline. Therefore, understanding mechanisms impairing baroreflexes with MetS will help determine appropriate therapeutic management to restore baroreflexes and promote stability of AP. Furthermore, because sex differences in the development of impaired baroreflexes with obesity have been reported, an understanding of how females are protected would provide valuable insights for underlying causes for early onset of impaired baroreflexes in obese males and eventual development of impaired baroreflexes in obese females. In this project, I utilized a rodent model of MetS, obese Zucker rats (OZR), to examine contributions of hypertension and hyperglycemia in the development of impaired baroreflexes in male OZR, and whether hypertensive female OZR have delayed onset of impaired baroreflexes because they have the ability to maintain glycemic control. Male and female OZR have excess weight gain from an early age because the mutation of a leptin receptor renders them insensitive to leptin's actions to regulate appetite and metabolism, promoting excess intake of standard chow and storage of ingested calories. Like obese humans, OZR develop dyslipidemia, hypertension, and insulin resistance that eventually progresses to type 2 diabetes, making them a suitable model for the consequences of MetS. Young adult male OZR (12-15 weeks) develop sympathetically driven hypertension with pronounced attenuation of baroreflex control of heart rate (HR) and sympathetic nerve activity (SNA) compared to juvenile OZR and lean Zucker rats (LZR). In male OZR, the development of impaired baroreflexes coincides with blunted activation of the NTS, the brain stem region that receives baroreceptor afferent inputs to promote baroreflex-mediated changes in HR and SNA, and this deficit likely yields diminished baroreflexes observed in young adult male OZR. In the first project I examined whether improvement of impaired glycemic control in young adult male OZR restores baroreflex-mediated bradycardia and activation of the NTS. Both type 1 and type 2 diabetic rats have impaired vagally-mediated activation of the NTS, in agreement with the reported loss of glucose's ability to enhance glutamatergic neurotransmission within the NTS of hyperglycemic, diabetic rodents. Male OZR develop insulin resistance at an early age, characterized by elevated insulin and triglycerides with impaired glucose tolerance but normal fasting hyperglycemia. We examined glucose homeostasis using chronic measures of blood glucose by telemetry in undisturbed rats because of previous reports of exaggerated stress responses. We observed that although young adult (12-14 weeks old) male OZR have normal fasting blood glucose, they are chronically hyperglycemic with access to food. Treatment of OZR with metformin or pioglitazone restored fed blood glucose levels with access to food and enhanced baroreflex-mediated bradycardia and activation of the NTS, as suggested by phenylehphrine-induced c-Fos expression. In contrast, treatment of LZR did not alter glucose or affect baroreflex-mediated bradycardia and activation of the NTS. Neither treatment reduced elevated AP and insulin in OZR, suggesting the lowering of blood glucose was effective for restoring baroreflexes in young adult male OZR, even in the face of hypertension. In the second project I examined whether the delayed onset of impaired baroreflexes in hypertensive female OZR could be due to their ability to maintain a normal blood glucose and baroreflex-mediated activation of the NTS. Premenopausal obese women protected from diabetes, suggesting they would be protected from deficits produced by hyperglycemia. I observed that intact baroreflex-mediated bradycardia in young adult female OZR extended to preserved sympathetic baroreflexes and baroreflex-mediated activation of the NTS in 12-15-week-old female OZR. Furthermore, although these OZR were hypertensive and hyperinsulinemic, fed glucose levels and glucose tolerance are comparable to LZR. In contrast, by 6 months of age, baroreflex-mediated bradycardia was blunted in female OZR. However, fed glucose was only mildly elevated and baroreflex-mediated activation of the NTS was comparable in OZR and LZR. These data suggest the ability to maintain glucose homeostasis in young adult female OZR coincides with a preservation of baroreflex-mediated bradycardia and activation of the NTS. However, the later development of impaired baroreflex-mediated bradycardia in female OZR occurs through mechanisms distinct from those observed in male OZR. The third project examined whether preventing hypertension in male OZR protected against the development of impaired baroreflexes and activation of the NTS. Treatment with losartan or hydralazine normalized baseline AP in male OZR without affecting hyperinsulinemia, dyslipidemia, or hyperglycemia. Furthermore, these treatments enhanced baroreflex-mediated bradycardia and activation of the NTS in male OZR. However, even when AP was normalized in male OZR, baroreflex-mediated bradycardia was still smaller in treated OZR compared to like-treated LZR, suggesting other mechanisms also contribute to the blunted baroreflexes. Together these studies suggest that the development of hyperglycemia and hypertension in male OZR contribute to impaired baroreflex-mediated bradycardia and activation of the NTS in male OZR. However, the ability of female OZR to maintain glucose homeostasis preserves baroreflexes despite the presence of hypertension and hyperinsulinemia. Furthermore, when female OZR later develop impaired baroreflex-mediated bradycardia, this deficit occurs by mechanisms that differ from male OZR, highlighting the need to examine both sexes for the development of cardiovascular and metabolic disorders.Item NEUROPLASTICITY IN THE NUCLEUS TRACTUS SOLITARIUS PRECEDES DEVELOPMENT OF FUNCTIONAL CHANGES IN AUTONOMIC REGULATION OF ARTERIAL PRESSURE IN OBESE ZUCKER RATS.(2013-04-12) Fu, GuangchaoPurpose: In juvenile OZR (7 wks) splanchnic sympathetic nerve activity (SNA), mean arterial pressure (MAP), and arterial baroreflex-mediated control of SNA are comparable to LZR. In contrast, in adult OZR (12-14 wks), baseline SNA and MAP are elevated and baroreflexes are blunted compared to age-matched LZR. Baroreceptor afferent nerves of adult OZR respond normally to rises in MAP, but direct stimulation of the afferent fibers evokes blunted decreases in SNA and MAP, suggesting changes in the brain contribute to impaired baroreflexes. Activation of the nucleus of the solitary tract (NTS), the brain stem site that receives baroreceptor inputs, by microinjection of glutamate evokes comparable decreases in SNA and MAP in juvenile OZR and LZR but blunted responses in adult OZR. In contrast, activation of the brain stem target of the NTS, the caudal ventrolateral medulla, evokes comparable responses in adult OZR and LZR, suggesting the NTS is the major site that is impaired in adult OZR. The present study sought to determine the time course and the phenotype of NTS neurons that may be altered in OZR to contribute to impaired physiological responses. Methods: Zucker rats (5-6 wk, 7-8 wk and 11-12 wk, 6/group) were transcardially perfused with 4% paraformaldehyde. Brains were harvested and fixed for 48 hours. Then the brains were cut in the coronal plane (30 microns) using a Vibratome and stored in cryoprotectant for later histological processing. To identify neurons undergoing neuroplasticity in the intermediate NTS, we performed immunohistochemistry for ΔFosB revealed by 3, 3'-diaminobenzidine. Results: At 5 wks OZR and LZR had comparable numbers of ΔFosB+ neurons in the NTS (203±30; 195±22, P=0.85). In contrast, at 7 wks and 12 wks OZR had significantly more ΔFosB+ neurons versus age-matched LZR (7 wks: 514.5±70; 207±24.5, P <0.05). (12 wks: 177±15.38; 88±15.76, P <0.05). The ΔFosB positive neurons were not catecholaminergic (immunoreactive for tyrosine hydroxylase). Conclusions: These results suggest noncatecholaminergic NTS neurons undergo neuroplasticity in the OZR prior to the onset of hypertension or impaired baroreflexes, and these changes persist in adulthood.Item The Role of Free Radicals in the Exercise Induced Resetting of the Arterial Baroreflex(2016-05-01) Moralez, Gilbert; Peter B. Raven; Robert T. Mallet; J. Thomas CunninghamThe arterial baroreflex’s (ABR) operating point (OP) pressure is reset upwards and rightwards from rest in direct relation to the increases in dynamic exercise intensity. However the interneural pathways and signaling mechanisms that lead to upwards and rightwards resetting of the OP pressure, and hence the increases in central sympathetic outflow during exercise, remain to be identified. Data from recent animal investigations have implicated nitric oxide (NO) as a modulator of central sympathetic outflow. For example, introduction of NO centrally dampens sympathetic outflow and there is a growing body of evidence that indicates that central NO is scavenged by centrally generated free radicals (FR), thereby, enabling increased central sympathetic outflow. Furthermore, during dynamic exercise, increases in centrally generated FRs formed by increased intensity-related oxidative metabolism and central angiotensin II (Ang II) production linked to exercise intensity related FR production suggests that FRs are candidate signaling molecules. Whether the primary site of the FRs signaling action occurs within the central nervous system (CNS) or is a result of peripheral chemo- or mechano-receptor input to the CNS remains to be established. Therefore, the aim of the proposed research is to investigate the role of FRs on arterial baroreflex resetting in human subjects. The first investigation of this project tested the hypothesis that combined central and peripheral FRs play a pivotal role in the exercise related resetting of arterial baroreflex control of arterial blood pressure and muscle sympathetic nerve activity (MSNA) in healthy subjects. The second investigation of this project tested the hypothesis that the Ang II linked FR production-mediated acute ABR-OP pressure resetting during exercise is located within the CNS. From these investigations we identified that: i) free radical production, particularly superoxide, plays a pivotal role in the exercise related rightward and upward resetting of the ABR-OP pressure and the reflex control of central sympathetic outflow; and ii) the major effect of Ang II on ABR-OP pressure resetting and control of central sympathetic outflow occurs centrally.